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      Fludrocortisone Is an Effective Treatment for Hyperkalaemic Metabolic Acidosis in Kidney Transplant Recipients on Tacrolimus: A Case Series


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          Background: Hyperkalaemia with metabolic acidosis is common but under-reported following kidney transplantation. Calcineurin inhibitors, such as tacrolimus, are widely used in the management of transplant patients and are associated with the development of hyperkalaemia. We report on 10 renal transplant patients, treated with fludrocortisone, following identification of hyperkalaemic metabolic acidosis. Results: All 10 patients were male aged (mean ± SD) 53.0 ± 13.2 years; 7 were Caucasian and 3 South Asian. Before and after fludrocortisone administration, respective (mean ± SD) serum potassium was 6.1 ± 0.4 mmol/L and 5.3 ± 0.3 mmol/L ( p = 0.0002); serum bicarbonate 18.5 ± 1.6 mmol/L and 20.5 ± 2.3 mmol/L ( p = 0.002); serum sodium 135 ± 4.6 mmol/L and 137 ± 2.2 mmol/L ( p = 0.0728); serum creatinine 181 ± 61 μmol/L and 168 ± 64 μmol/L ( p = 0.1318); eGFR 42 ± 18 mL/min and 46 ± 18 mL/min ( p = 0.0303); blood tacrolimus 10.1 ± 2.9 ng/mL and 10.4 ± 1.4 ng/mL ( p = 0.7975); and blood pressure 129 ± 15/79 ± 25 mm Hg and 126 ± 24/75 ± 7 mm Hg. Pre-fludrocortisone, there were 7 episodes of serum potassium ≥6.5 mEq/L, with 4 patients requiring admission for the treatment of hyperkalaemia. Following fludrocortisone, no patients had hyperkalaemia requiring inpatient management. Conclusions: Treatment of hyperkalaemic metabolic acidosis in transplant patients on tacrolimus with low-dose fludrocortisone resulted in rapid correction of hyperkalaemia and acidosis without significant effects on blood pressure or serum sodium. Fludrocortisone can be an effective short-term option for the treatment of hyperkalaemic metabolic acidosis in kidney transplant recipients on tacrolimus; however, patient selection remains important in order to reduce to risk of potential adverse effects.

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          Calcineurin Inhibitor Nephrotoxicity: A Review and Perspective of the Evidence

          Background: There is no doubt that acute calcineurin inhibitor (CNI) nephrotoxicity exists; however, chronic CNI nephrotoxicity is questionable at best. Methods: We reviewed the literature to identify original articles related to the use of CNIs in renal and nonrenal solid organ transplantation in order to examine the available evidence about their chronic nephrotoxicity and contribution to graft failure. Results: Early clinical experience and animal studies support the evidence of CNI nephrotoxicity. These findings evolved into the dogma that CNI nephrotoxicity is the major cause of late renal allograft failure. However, in transplanted kidneys the specific role of chronic CNI nephrotoxicity has been questioned. The emerging literature clearly highlights the lack of solid evidence for the role of CNIs as the sole and major injurious agents that cause chronic renal dysfunction and subsequent graft failure. Most of the evidence available to date is against complete CNI avoidance, and minimization appears to be a more viable strategy. It is becoming increasingly clear that the typical pathological lesions linked to chronic CNI use are highly nonspecific, and most of the chronic changes that have been attributed to chronic CNI nephrotoxicity are the consequences of previously unrecognized immunologic injuries. One needs to keep in mind that the potential risk of side effects of CNI use should be balanced against the risk of rejection. Conclusions: More research should focus on addressing the true causes of chronic graft dysfunction rather than focusing on the overexaggerated contribution of CNIs to late graft loss.
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            Distal tubular acidosis induced by FK506.

            This study was designed to investigate the effect of tacrolimus (FK506) and of cyclosporine (CsA) on tubular function in renal graft recipients. Patients were randomised after renal transplantation to immunosuppressive treatment with FK506 (n = 8) or CsA (n = 8). Patients had a mean age of 45.7 +/- 3.4 yr; there was no difference in age, sex, HLA status or CMV mismatches. Neither was there any difference in the frequency of episodes of acute kidney failure between the groups, nor was there a significant difference in the frequency of episodes of kidney rejection within the first year. The mean FK506 level at the time lay at 14.7 +/- 14.4 ng/mL whole blood, and the mean CsA level at the time of study was 162 +/- 25 ng/mL whole blood. We performed renal function studies 6 months after transplantation: CIn, CPAH, NaHCO3 loading, and Na2SO4 loading. There was no significant impairment of GFR in patients treated with FK506 with 53.6 +/- 2.5 mL/min as compared to 58 +/- 6 mL in group 2. Plasma renin activity (0.6 +/- 0.4 ng/mL vs 2.3 +/- 3; p < 0.01) and aldosterone (69 +/- 17 vs 157 +/- 28.2 pg/mL; p < 0.05) were significantly decreased during treatment with FK506. Fractional HCO3 excretion was low in both groups, indicating that bicarbonate reabsorption in the proximal nephron was unimpaired. Distal renal tubular acidosis was demonstrated in 4 patients of group 1 but in only 1 of group 2. Potassium levels were slightly increased in patients treated with FK506 (5.4 +/- 0.2 mmoL/L) as compared to cyclosporine (4.9 +/- 0.3 mmoL/L; p < 0.05). Distal hydrogen ion secretion, evaluated by the ability to increase urinary pCO2 in a highly alkaline urine, was impaired in patients treated with FK506 (U-B pCO2: 16.1 +/- 4 vs 36 +/- 5.8; p < 0.05) as compared to patients treated with CsA. The maximum acidification capability (NAE) was slightly lowered during therapy with FK506 (67.5 +/- 11.8 versus 86.6 +/- 16.5 mumoL/min, ns). We conclude that FK506 administration results in a decrease in the rate of hydrogen ion secretion by the collecting tubules. This defect was disclosed by the finding of a subnormal pCO2 in a highly alkaline urine. These results show that FK506 is able to induce distal tubular acidosis. Distal tubular acidosis is part of FK506 induced nephrotoxicity, the pathogenesis of this type of hyperkalemic metabolic acidosis found in patients treated with FK506 after renal transplantation has to be further elucidated.
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              Fludrocortisone Therapy in Renal Transplant Recipients with Persistent Hyperkalemia

              Hyperkalemia after kidney transplantation is a common electrolyte disturbance and the risk factors are multifactorial. Pharmacotherapeutic agents for chronic management of hyperkalemia in kidney transplant patients may be relatively contraindicated or provide suboptimal efficacy. Fludrocortisone, an endogenous mineralocorticoid mimics the actions of aldosterone, hence hyperkalemia reversal. We describe three- case series of persistent hyperkalemia with demonstrated benefit from fludrocortisone therapy. Our three renal transplant recipients with multiple emergency room visits for elevated serum potassium levels despite treatment with diuretics, sodium bicarbonate, and sodium polystyrene sulfonate responded well to fludrocortisones therapy. Upon fludrocortisone initiation and maintenance therapy, all three patients experienced a decline in serum potassium levels to normal reference range.

                Author and article information

                S. Karger AG
                March 2022
                16 November 2021
                : 146
                : 2
                : 190-196
                Renal Unit, St. Helier Hospital, Epsom and St Helier University Hospitals NHS Trust, Carshalton, United Kingdom
                Author information
                519670 Nephron 2022;146:190–196
                © 2021 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                : 29 June 2021
                : 13 September 2021
                Page count
                Figures: 1, Tables: 2, Pages: 7
                Clinical Practice: Case Report

                Cardiovascular Medicine,Nephrology
                Fludrocortisone,Type-4 renal tubular acidosis,Tacrolimus,Calcineurin inhibitor,Hyperkalaemia,Renal transplant,Metabolic acidosis


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